NZ204758A

NZ204758A - Eburnane-oxime ethers and pharmaceutical compositions

Info

Publication number: NZ204758A
Application number: NZ204758A
Authority: NZ
Inventors: C Szanti; L Szabo; G Kalaus; J Sapi; B Kiss; M Balazs; G Ezer; E Karpati; L Szporny
Original assignee: Richter Gedeon Vegyeszet
Priority date: 1982-06-30
Filing date: 1983-06-29
Publication date: 1985-12-13
Also published as: FR2529549B1; IL69010A; AU1639883A; GB8317616D0; GB2123413B; ES8501394A1; DK296883D0; NL8302288A; GR77526B; GB2123413A; ATA238683A; US4549020A; JPS5920282A; CA1199638A; CH656384A5; HU187140B; DE3323077A1; ES523685A0; PT76953B; PT76953A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £04758 2047 58 Priority Date(s): 30 ~ k - . Complete Specification Filed: cW Cass: .. ft ^^. Publication Date: A P.'rV. P.O. Journal, No: .1 NO DRAWINGS Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "Eburnane-oxime ethers, process for their preparation and pharmaceutical compositions containing them" -I-,WE RICHTER GEDEON VEGYESZETI GYAR RT. , of Budapest X. Gyomroi ut 21. Hungary, a Hungarian company, hereby declare the invention, for which 5/we pray that a patent may be granted to utt/us, and the method by which it is to be performed, to be particularly described in and by the following statement (followed by page IA > 204-7 5 8 Eburnane-oxiine ethers, process for their preparation and pharmaceutical compositions containing them The invention relates to new eburnane-oxime 5 ethers, process for their preparation and pharmaceutical compositions containing them. More particularly, the invention concerns new racemic and optically active eburnane-oxime ether derivatives of the geheral formulae (Xa) and/or (lb) 10 15 20 (la) (lb) 2^ whex-ein R"*" is alkyl having 1 or 2 carbon atoms, 2 R is alkyl having 1 to 6 carbon atoms, and tlio configuration of llio hydrogoxi in tlio ^-position 7 5 8 - 2 - and R is oc,oc and/or 13, IB or oc,B and/or 6 ,oc and acid addition salts thereof. The invention further relates to a process for the preparation of said compounds of the formulae (la) 5 and/or (lb) and acid addition salts thereof, by alkylating racemic or optically active eburnane-ccdme derivatives of the general formulae (Ha) and/or (lib) 10 (ZXa) 15 20 (lib • 2 25 wherein R and the configuration of the 3-hydrogen and 2 R have the same meaning as defined above, or acid addition suits tho roof, and if UosiroU, resolving Uxo racomio 204-758 compounds of the formulae (la) and/ox- (lb) and/or if desired, treating the racemic or optically active compounds of the formulae (la) and/or (lb) obtained by an acid. The new compounds of the formulae (la) and/or 5 (lb) pos sess valuable pharmaceutical activities, thus are potent CNS-tranquillants, smooth muscle relaxants, sedatives and hypnotic agents. The pharmaceutical compositions containing compounds of tho formulae (la) and/or (lb) or acid addition salts thereof as active 10 ingredients ux-e also within tho scope of the invention,, 1 2 In the above fox-iuulae R and R as alkyl groups having 1 or 2 and 1 to 6 carbon atoms, respectively represent straight or branched chained alkyl groups, e.g. methyl or ethyl and methyl, ethyl, n-propyl, iso-15 propyl, n-butyJL, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups, respectively. Starting compounds of the formulae (Ha) and/or (lib) are new. They can be prepared from the corresponding eburnamonine derivatives by animation, pref'sr-20 ably carried out with a tex-tiary g-alkyl nitrite, in the presence of a strong base. The alkylation of the racemic or optically active compounds of the formulae (Ila) and/or (lib) can for example be accomplished with a suitable dias'oallcane, 25 preferably d:i azomethano or diazoethane. The process according to tne invention is preferably performed in an organic solvent or solvent mixture inert wider the roaction conditions, preferably in a mixture of an aliphatic - k - 2047 alcohol and a halogenated aliphatic hydrocarbon, or In an aromatic hydrocarbon. The alkylation Is preferably carried out at a reduced temperatui-e, preferably between 0 °C and 5 °C, 5 In the process according to the invention the configuration of the hydrogen in the 3-P°sition and 2 R does not change, i,e, the configuration is the same in the end products of the general formulae (la) and/or (lb) as in the starting compounds of the formulae (ila) 10 and/or (lib) If desired, the compounds of the formulae (la) and/or (lb) may be converted into theii" acid addition salts. Suitable acids for this purpose include inorganic acids such as hydrogen halides, e,g. hydrochloric acid, 15 hydrogen bromide; sulfuric acid, phospttozic acid, nitric acid; perhaloic acids; e.g. perchloric acid, etc,; organic carboxylic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, jnaleic acid, hydroxy-maleic acid, fumar;i.c acid, sxiccinic acid, tartaric acid, 20 ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnainic acid, benzoic acid, phenylacetic acid, ^-amino-benzoic acid, jj-hydroxy-benzoic acid, j>-amino-salicylic acid, etc,; alkylsulfonic acids, such as methanesulfcnic acid, ethanesulfonic acid, etc,; 25 cycloaliphatic aoicis, e,g, cyclohexylsulfonic acid; arylsulfonio acids, e.g, 2>-^&luene-sulfonic acid, naphthyl-suli'omi c acid , wri.LX'ujryli <' uc J <.t, ofco, ; ainJ.no acids, such as aspaiaginic acid, glutaminie acid, N-acetyl-asparaginic 204758 acid, N-acetyl-glutaric acid, etc. The salts are generally prepared in an inert organic solvent, for example in an aliphatic alcohol having 1 to 6 carbon atoms by dissolving the racemic 5 or optically active compounds of the formulae (la) and/or (Xb) in said solvent, adding the corresponding acid into the solution while the pH of the mixture becomes slightly acidic (pH 5-6) and subsequently separating tho px'ecipitated acid addition salt from the 10 reaction mixture by a suitable method, e.g, by filtration. The racemic compounds of the formulae (Xa) and/or (lb) can be x*esolved by known techniques but optically active end product of the formulae (la) and/or 15 (lb) may also be prepared by starting from the corresponding optically active compounds of the formulae (Ila) and/or (lib), Racemic prodxtcts of the formulae (la) and/or (Xb) are prel'erabiy prepared directly from tne corresponding racenuc starting compounds of the formulae 20 (Ila) and/or (lib) while the optically active compounds of the formulae (la) and/or (lb) are preferably obtained starting from the corresponding optically active compounds of the formulae (ila) and/or (lib). If desired, the I'acemic or optically active 25 compounds of the formulae (la) and/or (lb) or acid addition salts thereof may bo subjected to further purification, o, roiM'ys Lullivsulion, .Tho solvents used for recx-ystalligation aro selected in accordance with the - 6 - 204758 solubility and the crystallizability of the compound to be recrystallized. The active ingredient of the formulae (la) and/or (lb) or pharmaceutically acceptable acid addi-5 tion salts thereof can be converted into pharmaceutical compositions for parenteral or enteral administration by admixing them with solid and/or liquid carriers and/or further additives conventionally used in the preparation of pharmaceutical compositions. As a carrier for example 10 water, gelatine, lactose, starch, pectine, magnesium stearate, stearic acid, talc, vegetable oils, e.g. peanut oil, olive oil, etc. can be employed. The compositions may be finished in the form of solid, e.g, tablets, lozenges, drag^es, capsules, such as hard gelatine capsules, 15 suppositories, etc, or liquid, e.g, oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc, formulations. The quantity of the solid carrier can be varied within a wide range but preferably is about 20 between 25 ing. and 1 g. Tho pharmaceutical compositions optionally contain also conventional pharmaceutical additives, such as preservatives, stabilizing, wetting, emulsifying agents, salts capable of adjusting the osmotic pressure, buffers, flavouring agents, aroma 25 agents, etc. Optionally further pharmaceutically active compounds can also be present in the formulations. Tho pharmaceutical eompositions are profei'ably manufticturod in dosugo units, suitable for tho desired 2047 58 - 7 - route of administration, Tlie pharmaceutical compositions may be prepared by conventional techniques, which comprise for example screening, admixing, granulating, pressing or dissolving of the components. The compositions obtained 5 can be subjected ta further operations conventionally used in the pharmaceutical industry, for example sterilisation. Further details of the present invention are to be found in the following Examples which are, however, 10 by no means intended to limit the scope of the protection s ought, Example 1 Z- (+) -14-0xo-15-methoxyimino-eburnane ( 3cc, l6oc) 15 and its hydrochloride 4.00 g. (12.4 minoJe s) of Z-(+ )-^-oxo-^-hydroxy-imino-eburnane ( 3oc , l6oc) are dissolved in a mixture of 40 ml, of methanol and 20 ml. of dichloroinethane. To the solution obtained a solution of diazoraethane, prepared from 2,8 g, 20 of N-nitrozo-N-methyl-urea according to Vogel: Practical organic Chemistry, 3rd Edition, 971 in 60 ml. of dichloroinethane is added at 0 °C and the reaction mixture is allowed to stand for 24 to 36 hours. The reaction is monitored by thin layer chromatography (KG-F^^, di-25 chloromethane :methanol=:20 :i) . The R^-value of the end product is higher than that of the starting material. Tho solvent is eliminated in vacuum and the residual oil weighing 4.5 S* is dissolved in 15 nil. of 2 0475 6 methanol. The pH of the solution is adjusted to 2-3 by hydrochloric acid in methanol and it is allowed to crystallized. 3.23 g. of the hydrochloride of the title compound are obtained. 5 Yield: 69.7 % Melting point: 248 °C (decomp.) 546 = + 39°; M = +37.5 (c=l, chloroform). IR spectrum (lffir): 1715 (CO), 1642 cm-1 (C+N) (CDCl^): 8.48-7.75 (4H, m, aromatic); 4,08 (3H,s, 10 3-H) ; 1.02 (3H,t,J=7.5 Hz, CHgCH ). Mass spectxouu (m/3 %) : 337 (M? loo) , 336 (63.5), 308 (47.7), 277 (24.2), 267 (18.2). Example 2 E-(.)-14-Oxo-15-methoxyiniino-eburnane ( 3oc, l6oc) and its hydrochloride 200 mg. (0.62 nunoles) of E-(-)-l4-oxo-15-hydroxy-iniino-eburnane( 3oc ,l6oc) obtained in a smaller amount by oximation of vincamone are reacted with 4 ml. of a 20 solution of diazomethane in diohloromethane (preparation according to Vogel: Practical Organic Chemistx^y 3rd Edition, 971) in a mixtxure of 2 ml, of methanol and 1 ml. of dichloromethane at about 0 °C, with stirring, for one and a half houx-s. The reaction is monitored by thin 25 layer chromatogx'aphy (KG-G, dichl0x"0iuethane :inethanol = =20:1), The R^-value of the end product is higher than Lhul of llio atari, lay compound. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 20475& The solvent is eliminated in vacuum and the residue, weighing 240 mg. is purified by preparative layer chromatography (KG-60-PF2^^+^^g, dichloromethane: •.methanol = 100:6, elution with a 10:1 mixture of 5 dichloromethane and methanol). By evaporation of the eluate 187 mg, (89.6 %) of an oily product are obtained, which is then dissolved in 1.5 nil. °f methanol. The pH of the solution is adjusted to 3 with hydrochloric acid in methanol and crystallization of the product is induced 10 by adding 4 ml, of ether, 150 mg, of the title compound are obtained as a hydrochloride. Yield: 72.3 % Melting point: 190 to 192 °C (methanol) ■*■•5 ^546 = "^3° ( c=-0. 8, chloroform) XR spectrum (KBr) : 1675 (CO) , 1640 cm (C+N). Mass spectrum (111/e, $) : 337 (M+ , 100), ^II-NMR spectrum (CJDCl^): 8,46-7.30 (4H, m, aromatic); 4,45 (1H,S,0C1I); 4.26 (111, s, 3-H) , (3H,t,J=7.2 Hz, 20 , c-ch2-ch3). 2 04758 Claiiiiio ^VHAT^/WE CLAIM IS;.

1. Optically active ox* raceinic eburnane-oxiine ethers of the formulae (la) and/or (lb)

10

(la)

15

(lb)

20

25 in which

R represents an allcy.L group having 1 or 2 carbon atoms,

- 11 -

20475S

1{ represent a an alley 1 group having 1 to 6

carbon atoms and tho configuration of the hydrogen in the 3-p°sition

2

and tho R group is oc ,oc and/or B,B or oc, 13 and/or 13, oc 5 and acid addition salts thereof.

2. Pharmaceutical compositions, which comprise as an active ingredient at least one racemic or optically active compound of the formulae (la) and/or (lb) (as defined in claim l) or a pharmaceutically acceptable 10 acid addition salt theroof, in admixture with inox^t solid or liquid pharmaceutical carriers and/or additives.

'J, Pharmaceutical compositions as claimed in claim 2 in fox-ms suitable for parontoral or enteral administx-ation.

15 U, Phax-maceutical compositions as claimed in eitliei' of claims 3 und U in dosage unit form.

5. A process for the preparation of racemic ox* optically active eburnane-oxime ether derivatives of the formulae (la) and/or (lb) 3s hereinbefore defined (wherein R, R and the

2

20 configuration of the 3-hydrogen and R are as defined in claim l) and acid addition salts thereof, which process comprises alkylating raceinic or optically active eburnane--oxime derivatives of the general fox*uiulae (XXa) and/or (lib)

- 12 -

2047m

10

(Ila)

15

(lib)

wherein R and tho configuration of the 3-hydrogen and

2 ...

R have the same meaning as defined in claim 1, or acid

25 addition suits thereof, and if desired, resolving the rucomic or op(.lcally uotivo compounds of tho foniiulao (la) und/ox- (lb) obtained und/or if dosirod, troating

- 13 - 204*753

the racemic or optically active compounds of the formulae (la) and/or (lb) obtained by an acid to form an acid addition salt.

6. A process as claimed in claim 5 wherein the alkylation is carried out with a diazoalkane.

7. A process for the preparation of pharmaceutical compositions which comprise as active ingredient at least one racemic or optically active compound of the formula (la) and/or (lb) substantially as specifically described herein.

8. Products of the process of claim 7.

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